Preparation of etio-steroid acids



Patented Aug. 12, 1952 PREPARATION OF ETIO-STEROID ACIDS Percy L.Julian, Maywood, and Edwin W. Meyer,

Chicago, 111., assignors to The Glidden Company, Cleveland, Ohio, acorporation of Ohio No Drawing. Application April. 1 1949,

Serial No. 85,027

13 Claims. 7 (c1. zen-397.1)

The present invention relates to a method "of preparing etio-steroidacids.

Etio-steroid acids are valuable intermediates in the preparation ofvarious hormones, and Wilds and shunk, JACS '70, 2427 (1948) haverecently published a method for converting 3- keto-4-etiocholenic acidinto desoxycorticosterone. The prior methods, however, of preparingthese etio acids have resulted in relativelylow yields. Hoehn and Mason,J.'A. C. S. 60, 1493 (1938) obtained a 14.5l7% yield of 3(a), 1201)dihydroxy etiocholanic acid from the 3,12-dihydroxy bisnorcholanic acidand Steiger and Reichstein, Helv. Chim. Acta 20, 1040 (1937) obtained a9% yield of 3-acetoxy-5-etiocholenic acid based upon3-hydroXy-5-bisnorcholenic acid.

These yields leave much to'be desired and it is accordingly an object ofthe present invention to provide a process for producing etio-steroidacids in improved yields. j

A further object of the invention is to provide a novel method for thepreparation of .etio-steroid acids.

An additional object is to provide a method for preparing etio-steroidacids by a novel method of degradation of the side chain of steroids.

Another object is to provide an improved process for preparing3-keto-4-etiocholenic acid.

Other objects will be apparent from the following description.

It has been found that the foregoing objects can be accomplished by thedecomposition of ternor-steroid quaternary ammonium halides intol'l-vinyl steroids and then oxidizing the vinyl grouping to a carboxylgroup. vThe'quaternary ammonium compounds are conveniently formed fromthe bisnorsteroid acids by first preparing the bisnor amine via theCurtius degradation, U. S. Patent No. 2,108,646, and then preparin thequaternary ammonium halide by exhaustive methylation of the amine, suchas is described in copending application Serial No. 773,526, ,filedSeptember 11, 1947, now Patent No. 2,561,378.

The decomposition of the quaternary ammonium halide may be accomplishedby treatment with alkaline hydroxides such as potassium hydroxide orbysilver oxide followed by pyrolysis to decompose the quaternary baseformed, as described in copending application Serial No. 770,- 336,filedAugust 23, 1947.

Th'eoxidation of the A -steroids may becarried out using any suitableoxidizing medium. Ozone has been found preferable in many cases. Othersuitable oxidizing agents, such as chromic acid .and permanganate. can.be, used, however.

Where there are nuclear double bonds; it is dechainoxidation to beaccomplishedin good yield.

The application of the above procedures has enabled us to produce3-keto-4-etio-cholnic acid in yields of 33% based on3-acetoxy-5-bisnorcholenic acid and provides a feasible economic processfor the preparation of this etio acid.

The following examples are illustrative:

Example 1 3--aceto:1:y-20-aminof-5-pregnene. In a flask protected with acalciumchloride'tube, a suspension of 50.0 g. of3-acetoxy-5-bisnor-cholenic acid in 1000 ml. of-anhydrous ether wastreated 'with 29 ml. of freshly distilled thionyl chloride. After theaddition'of a few drops of 10% pyridine'in benzene, the mixture wasswirled occasionally. The acid dissolved within one-half hour; After twohours, the solvent was removed in vacuo with'gentle warming. To removethe last traces of thionyl chloride, the residue was dissolved successively in several small portions of dry benzene and this solvent wasremoved in vacuo. The acid chloride remained as a white, crystallinecake.

The acid chloride was dissolved in 900 m1. of acetone and chilled in anice-bath to 10. A solution of 16.0 g. ofsodium azide in ml. of water wasthen added dropwise, withmechanical stirring, at such a rate that thetemperature of the solutionwas maintained .at '10-132 After fifteenminutes of stirring, 1000 ml. of ice cold Water was added and the whitecrystallineazide was filtered. .Themoist cake which weighed 160 g. wasadded toa mixture of 1000 ml. of glacial acetic acid and 152 ml. ofwater. .The mixturewjas warmed on a steam-bath with swirling. At about38 nitrogen was evolved and the azide wentinto solution. .Afterheatingfor-one hour atf60-,65;, the solution was steam distilled (about 2-3 l.o: l distillate). To the residual mixture, while. still hot, a solutionof g. of sodium hydroxidein'300 ml. of water was addediportionwise withgood agitation. Upon cooling, the 3-acetoxy-20-amino- 5-pregnene acetateformed needle-like crystals. The mass was filtered, washed with a smallquantity of coldwater and dried. The acetate weighed 51.7 g. (96%) andmelted at 200-205 after s e n li tly. a abo t 1 i h gee terial whichcontains a small quantity of sodium acetate is of sufficient purity forfurther experimentation.

Example 2 orous but this subsided to a slow steady rate.

The mixture was diluted with water and extracted with ether after theaddition of dilute hydrochloric acid. The aqueous layer containingsuspended insoluble hydrochloride was separated and combined with thewater washings of the ethereal layer. The aqueous mixture was madealkaline with dilute sodium hydroxide and extracted well with ether. Theether solution was washed with water and dried. 'Uponremoval of solvent,there remained 17.8 g. (92%) of a white, crystalline residue melting at155-175 which was sufiiciently pure for: the preparation of thequaternary halide. For-analysis, however, several recrystallizationsfrom :a. small volume of ether gave glistening plates which melted at1845-1875"; (a) 5.0il- 77 .2 mg. made up to 5 ml. withchloroferries-0.7721, 1,

7 Example 3 3 acatowy 5 4 ternor r cholenyltrimethylammonium.iodide-.--Ten and four-tenths grams of the crude 3-acetoxy-dimethylamineof Example 2 was dissolved in 40 ml. of warm benzene, chilled andtreated with 6. ml. of methyl iodide. Thesolption was refluxed-for twohours. During this period a heavy. crop of crystalline materialseparated; The mixture was slurried with ether, filtered, and the solidwashed with ether. The mother liquor was concentrated to remove etherand. was retreated with methyl iodide in the same fashionto obtain asecond crop of material. The total-yield of white, crystallinequaternary iodide amounted to 12.7 g. (89.2%) M. P. 255-265", dec.Recrystallization from methanol gave plates which decomposed at 270.

Anql .-Calcd. for C26H4402NII C, 58.97; H, 8.38. Found; o, 5 H, 823,

Y Example 4 tel;3 hyclrory-5,20 pregnadiene.-A solution or 7,2'g'.,oi3iacetoxy-5-ternor-cholenyltrimethylammoniumiodide ina mixture of 14.0g. of potas'sium hydroxide; 15ml. of Water and 55 ml. of ethylene glycolwas boiled, allowing the water vapor'to'escape until the solutionreached a temperature of about. 135. Then heating was continuedfunderreflux. Slowly oil globules separated and trimethylamine was liberated.After six hours the mixture was chilled, diluted with water andextracted with ether. The ether soluson was washed'with water, dried andtreated with glacial acetic acid until a slight excess was present; Themixture was chilled and the while solid wasseparated by filtration andwashed with ether (saved from amine recovery). The ether filtrate wasthen washed with dilute alkali, water 'and dried. Upon concentrationthere remained 2.8g. (approximately 65% discounting water ofcrystallization) of a crystalline, white solid which lost water at1l0-120 and melted l30l33. Several recrystallizations from methanol gavel-Calcd. for osmium; 0,, 77.47; H, 10.66.

colorless plates which frothed at 125-127" and melted 138-4395. Uponstanding exposed to the atmosphere these crystals became opaque andslowly disintegrated; ((1) i1 (46.0 mg. made up to 5 ml. withchloroform, a0 78, l. 1 dm.) For analysis the product was dried for fivehours at 1 mm. over boiling chloroform.

AnaZ.-Calcd. for 021E320: C, 83.95; H, 10.72. Found: C, 83.64; H, 11.00.

The solid acetate, 3-hydroxy-5-ternor-cholenyldimethylammonium acetate,which was recovered from the reaction mixture weighed 1.4 g. Accountingfor this material which may be reused. the yield of the pregnadiene isUpon titration of the pregnadiene in chloroform solution with a solutionof bromine in chloroform, this substance absorbed the equivalent of twomoles of bromine per mole of compound without liberation of hydrogenbromide. The first mole was absorbed more rapidly than the second but nosharp end-point existed between the two.

Treatment of the B-hydroxy-pregnadiene with acetic acid-acetic anhydrideat steam-bath temperature for one hour afforded 3-acetoxy-5,20-pregnadiene. This material after two recrystallizations from methanolexisted as white prisms which melted at 1325-135". ((0 76.8:l (62.5. mg.made up to 5 ml. with chloroform, a0.96, Z, 1 dm.).

Anal-Calcd. for CzzHssOz: C, 80.64; H, 10.01. Found; (1.80.53; H, 9.94.

.(b) 3.-hydroxy-5,20 pregnadiene has also been prepared by conversion ofthe quaternary iodide to the ammonium hydroxide withmoist silver oxideand. subsequent pyrolysis of the quaternary base. In one experiment, 1.5g. of the iodide was treated in 50- ml. of methanol with moist silveroxide prepared from 7.5 g. of silver nitrate. After twelve hours theoxide was separated and the pale yellow filtrate was concentrated invacuo. The residue was pyrolyzed at 210 for fifteen minutes at '1 mm. Itwas then dissolved in ether, washed with dilute hydrochloric acid andwater and dried. The gum which remained after removal of ether wascrystallized from petroleum ether' (B. P. 35-60% g 0.2 g. of white solidmelting at 134 after losing solvent at 113-116".

(0') Decomposition of the quaternary base was also efiected by refluxingit in methanolic potassium hydroxide solution. This procedure was alsoeffective in converting the quaternary iodide directly into the dienewithout employing moist silver oxide for the preparation of theintermedie ate base. However, the last two methods gave erratic resultsespecially when applied to larger batches. Substitution of ethanol formethanol did not alter the situation.

((1) 3 acetoxy 5 ternorcholenyl trimethyl ammonium bromide wasdecomposed in much the same fashion as in the case of the iodide toyield 3-hydroxy-5,20-pregnadiene in quantity of the same order as above.

Example 5 3-keto-4,20-pregnadiene.-Nine grams of 3-hydroxy-5,20-pregnadiene was dissolved in a mixture of ml. of tolueneand 54 ml. of cyclohexanone and then a few ml. of toluene was distilledin order to remove traces of moisture. After the addition of 9.2 g. ofaluminum isopropoxide in 60 ml. of hot toluene, the solution wasrefluxed for one hour. The solution was then chilled, diluted withdilute hydrochloric acid and extracted with ether. The extract waswashed with water, concentrated and then steam distilled. The residuewas taken up inether, washed with water, dilute sodium hydroxidesolution and water. The pale yellow, crystalline residue re.- mainingafter the removal of ether from the dried solution was recrystallizedfrom a concentrated methanol solution. The product, 7.3 g. (81.6%) ofpale yellow prisms, melted at 120-125". This material is soluble inether, acetone, methanol, hexane and petroleum ether (B. P. 35-60).After it was recrystallized several times from a concentrated methanolsolution, the diene, practically colorless prisms, melted at123.5-126.5: ((1) 3 +106i-1 (82.5 mg. made up to 5 ml. with chloroform,a+1.75, Z, 1 dm.).

Anal.-Calcd. for Gail-I300: C, 84.52; H, 10.12. Found: C, 84.56; H,10.13.

3-keto-4,20-pregnadiene formed a white, crystalline semicarbazone whichmelted at 243-244, dec., after recrystallization fromchloroformmethanol.

Anal.-'-Calcd. for C22H33ON3: C, 74.32; H, 9.37. Found: C, 74.13; H,9.20.

ExampZe 6 3-keto-4-etz'o-cholenic acid.-A solution of 2.0 g. of3-keto-4,20-pregnadiene in 60 ml. of chloroform was ozonized (4.5% O: byvolume of 0.5 1./min.) for ten minutes at ice-bath temperature. Thesolution Was then steam distilled and the residual waxy solid dissolvedin ether. The ether solution was washed with water and then extractedwith cold dilute sodium hydroxide solution. Upon acidification of thealkaline solution with dilute hydrochloric acid, a white, crystallinesolid separated. The solid was filtered, Washed with water and dried;1.2 g. (56.6%), M. P. 235-250. After recrystallization fromacetonehexane and from acetone, the acid melted at 250-255". Thismaterial showed no depression in melting point when mixed with anauthentic sample of 3-keto-4-etio-cholenic acid prepared by theoxidation of 3-hydroxy-5-etio-cholenic acid. Reozonization of theneutral fraction yielded an additional quantity of etio-acid.

Example 7 3-p-toluenesulfonozcy 5,20 pregnadieae. A 5.8-g. sample of the3-hydroxy-diene of Example 4 was dissolved in 13 ml. of pyridine. Bywarming, on the steam-bath, 5.8 g. of p-toluenes'ulfon'yl. chloride wasdissolved in this solution. The mixture was allowed to stand overnight,then diluted with water and extracted with ether. The ether solution waswashed successively with dilute hydrochloric acid, water, dilute sodiumcarbonate solution, The residue remaining after removal of ether fromthe dried solution was crystallized from 1 ether-petroleum ether (B. P,35-60) There resulted 7.4 g. (8 of White solid which melted at 94-97".After one crystallization from benzene-petroleum ether and another frompctroleum ether, the colorless needles melted at 93.5-96: (a) 65i1 (65.0mg. made up to 5 ml. with chloroform, a-0.84, Z, 1 dm.).

Anal.-Calcd. for C28H3803SI C, 73.96; H, 8.42. Found: C, 74.14; H, 8.39.

EazampZe 8 separated by filtration and washed with 150 ml.

of petroleum ether. The filtrate was concentrated in vacuo to 3.2 g.(88.5%) of a colorless sirup: (a) +28.6:t2 (43.7 mg. made up to 5 ml.

with chloroform, a+0.25, Z, 1 dm.).

AnaZ.-Calcd.for (3221-1340: C, 84.01; H,--10.91. Found: C, 83.65; H,10.72.

Example 9.

Methyl 3-methoa2y 5 etio choZenate.-To a stirred solution of 2.5 g. offi-methoxy-A -ipregnadiene in 50 ml.- of pyridine and 5 ml. of

water, 5.0 g. of powdered potassium permanganate was added portionwiseover a period of three hours. The manganese dioxide was filtered andwashed with pyridine and water. The filtrate which remained clear upondilution with water was acidified with dilute acetic acid and extractedwith ether. The ether solution was washed with cold dilute sulfuricacid, with water and dried. The sirup which remained upon removal ofether was dissolved'in 50 ml. of methanol. Fifteen drops of concentratedsulfuric acid was added and the solution was refluxed for three andone-half hours. Water was added cautiously to the chilled solution untilcrystallization began. After completion of crystallization, the whitesolid was filtered, washed with aqueous methanol and dried. The solid,1.5 g., melted at -128. Several recrystallizationsfrom a concentratedmethanol solution gave 1.0 g. of white needles melting at 133-134, ((1)23:2 (44.3 mg. made up to 5 ml. with chloroform, a, 0.20, Z, 1 dm.).

AnaL-Calcd. for C22H34O3: Found: C, 76.10; H, 9.71. 7

The constitution of this etio-ester was proven by an independentsynthesis. 3-acetoxy-5-etiocholenic acid was converted to the acidchloride with thionyl chloride in dry ether. The acid chloride whenrefluxed in methanol for a short period gave methyl3-hydroxy-5-etio-cholenate (M. P. 175-178). The former upon refluxing inmethanol yielded, as indicated by mixed M. P., the same compound asdescribed above, namely, methyl 3-methoxy 5-etio-cholenate.

Example 10 3(a),12(a) -diacetozcy-ZO-aminogiregnane. A solution of 7.2g. of 3(a) 12(a) -diacetoxy-bisnorcholanic acid in 20 ml. of dry benzeneand 40 ml. of dry ether was treated with 4.2 ml. of freshlydistilledthionyl chloride. After standing at room temperature for one hour andforty minutes, the solvent was removed in vacuo with gentle warming. Thelast traces of thionyl chloride were removed by sweeping out, in vacuo,with several small portions of benzene. At this stage the acid chloride,which had begun to crystallize, was dissolved in m1. of acetone. Thesolution was chilled in an ice-salt-bath to 05 and treated drop-wise,with mechanical agitation, over a period of ten minutes with ,a solutionof 2.3 g. of sodium azide in 10 ml. of water. Sodium chloride separated.After an additional twenty minutes of stirring, 200 ml. of cold waterwas dribbled in a one-m1- with continued; stirring. The crystallineazide (a sample; of; this material melted at 86-90% dec.)

was then filtered, washed with cold water and suspendedin 130 ml. of 80acetic acid. This mixture was heated to 50-60" and held therefor onehour. The azide dissolved rapidly and then decomposed with evolution ofnitrogen. The solution was filtered, steam distilled for .thirtyminutes, filtered again and made alkaline with cold dilute sodiumcarbonate solution. The amine was extracted with. ether and washed withwater. Upon removal of solvent in vacuo from the dried solution thereremained 6.2 g. (96.7%) of yellow amorphous material. Attempts tocrystallize this material have not been overly successful. A smallsample when crystallized from ether and etherpetroleum ether (B. P.35-60") melted at 207-209 but was not analytically pure.

The crude amine readily gave an acetamide upon treatment with aceticanhydride in acetic acid; 800 mg. with. 4 ml. ofacetic acid and2 ml. ofacetic anhydride gave 910 mg. of amide melting at 210-220". Afterseveral recrystallizations from aqueous methanol, it melted at 200-221.

AnaZ:-Calcd. for CzqHtaOsN: C, 70.24; H, 9.60. Found: C, 7.14; H, 9.44.

A sample of the crude azide upon warming with ethanol formed theurethan. After several recrystallizations from aqueous ethanol, itmelted at 172-173 AnaZ.,-Calcd. for CzaHmQs-Nfi Cr, 68.39; H, 9.22.Found: C, 68.23; H, 9.23.

Example 11 3(a), 12 (a)-diacetoary-Z-dimethylaminopregnane.-A mixture of5.2 g.. of the crude 20- aminopregnane of Example 10, 6 ml. of 90%-form-io acid. and 4v ml. of 35% aqueous formaldehyde was heated onthesteam-bath under reflux for four hours. The orange liquid was pouredinto cold dilute sodium hydroxide solution, and extracted with ether.washed with water, dried and concentrated in vacuo. There remained 5.5g. (99%) of an orange glass. This material when crystallized frompetroleum ether (B. P. 35-60) gave 3.0 g. of white. solid, M. P. 115-25" (cloudy). The residue (2.5 g.) in the mother liquor-was alsoreserved for further processing. Several recrystal lizations of thesolid material from, petroleum,

ether. gave small, white needles melting at AnaZ.-Calcd. for C21H45O4N:C, 72.45; H, 10.14. Found: C, 72.71; H. 10.52.

From one run there was isolated a small pot-- tion of material meltingat l57-l74.. Several recrystallizations from acetone gave fine, whiteneedles melting at 184-1875". This material analyzed for anacetoxy-h-ydroxy-20-dimethylaminopregnane;

Anal.-Calcd. for CzsHlsOaN: C, 74.03; H, 10.68. Found: C, 73.90; H;10.57.

Example 12 3 (c) 12(11) -diaCt017y-ZU-PTZQMJQRGe-A 2.2-g. sample of thecrystalline 20-dimethylaminopregnane of Example 11 was dissolved in 20ml. of benzene, treated with ml. of methyl iodide and refluxed for ,twohours. The solution was diluted with. ether, chilled, and the solidmaterial The ether solution was ternorcholanyldimethylamine ture wasrefluxed (temperature of boiling solu.--

tion about 135) for seven and one-half hours, diluted with water andextracted with ether. The ether solution was then washed with water,dilute hydrochloric acid, water and dried. Concentration of the solutiongave a pale yellow glass. This was dissolved in 10 ml. of acetic acid- 3ml. of acetic anhydride and treated with 1 ml. of 5 N perchloric acid inacetic acid at ice-bath temperature and then allowed to stand forthirty: Upon dilution with water, a white The non-crystalline fraction(2.5 g.) of the,

diacetoxy 20 dimethylaminopregnane, when treated as described above gave1.4 g. (62.2%) of crystalline material melting at 162l75.Recrystallization from methanol raised the melting point to 184- Example1 3 (a) 3(a), 1-2(a)-diaceto:cyetio-cholanic acid. A solution of 1.0 g.of 3(a), 1-2(a)-diacetoxy-.20- pregnene in 30 ml. of acetic acid wasozonized for thirty minutes (4.5-5% 0:; at 0.5 l./min.). The solutionwas treated with, zinc dust, warmed, filtered and steam distilled afterthe addition of a few ml. of 30% hydrogen peroxide. The residue wasdissolved in ether and, washed with water. The ether solution was thenextracted with cold dilute sodium hydroxide solution. The neutralmaterial remaining in the ether was retreated with ozone and worked foracidic material. to the alkaline solution a solid separated. This wasfiltered, washed with water and dried. It was then acetylatedin 8 m1.of'acetic acid with 3 ml. of acetic anhydride employing 1 ml. of 5 Nmelted at 195-l99 (reported 196-198).

(1)) Oxidation of the 3(a), 12(1) -diacetoxy-20- pregnene with chromicacid in acetic acid ave the same etio-cholanic acid as in 13(a).

Example 14 4.2 g. of 3-acetoxy-allo-ternorcholanylamine acetate wasmixed with 3 g. of. formic acid and 2 g. of 35% aqueous formaldehydesolution and heated on 'a steam-bath for four hours. The solution wasthen concentrated in vacuo, diluted with 5% hydrochloric acid andextracted with ether. The acidic aqueous layer was made alkaline with10% NaOH and extracted with ether. The ether extract was Washed withwater and dried. The residue after removal of solvent was crystallizedfrom benzene. The crude 3- acetoxy-allo-ternorcholanyldimethylaminemelted at 147-153 C.

A solution of 0.5 g. of the 3-acetoxy-alloin benzene was mixed with asolution of 5 g. of methylbromide in 5 cc. of benzene and the mixturerefluxed for five hours. As heating progressed the solution becamecloudy and then a solid separated. After dilution with ether, the whitesolid was separated Upon addition of dilute hydrochloric acid,

and washed well with ether. The product 3- acetoxy alloternorcholanyltrimethylammonium bromide weighed 0.4 g., was quitesoluble in methanol but may be recrystallized from a coldconcentrated-solution.

The quaternary ammonium bromide may then be treated as in Example 4 toform the 3-hyfdroxy- 2o-allo-pregnene; upon ozonolysis yields the3-hydroxy-etio-adid.

" The reactions involved in the foregoing examples as they apply to theC-l7 substituent may be illustrated as follows, where R. represents anetio-steroid radical:

It will be appreciated that the foregoing examples are merelyillustrative and that many modifications may be made therein withoutdeparting from the spirit and scope of the invention. For example, inplace of the iodides, the chlorides and bromides may be used. These maybe prepared by treating the corresponding dimethylamines with methylbromide and methyl chloride in substantially the same manner as for thepreparation of the quaternary ammonium iodides. The chlorides andbromides may then be converted to the corresponding bases in the samemanner as described for the chlorides.

In the specification and claims the term etiosteroid acids is intendedto refer to steroid acids having a carboxyl group attached to the17-carbon atom of the steroid nucleus.

The term bisnor-steroid acids is intended to refer to steroid acidshaving the a-carboxy ethyl group, e. g.

attached to the 17-carbon atom of the steroid nucleus.

The term "ternorsteroidyl is intended to refer to a radical in which theethylidene group, e. g.

I OH- 1 0 .dimethylpolyhydrophenanthrene steroid having ,as the sole,substituents on the 17-carbon atom .of thesteroid nucleus hydrogen memegroupmg, I f v 'HpoHa' V c mompx' wherein'jXds, a halogen selected fromthe group consisting Of chlorine, bromine and iodine, with a metalcompound selected fromthe class con sisting of alkali-metal hydroxidesand silver oxide to form the quaternary ammonium'bases, followed by heattreatment to split off trimethylamine and water to yield a A -pregnene,and oxidizing the thus formed vinyl group to a carboxyl group andthereby forming an etio-steroid acid.

2. The process of claim 1 in which the halogen is iodine.

3. The process of claim 1 in which the halogen is chlorine.

4. The process of claim 1 in which the halogen is bromine.

5. The process of claim 1 in which the steroid nucleus is saturated.

6. The process of claim 5 in which the oxidation is anozonization.

7. The process of preparing etio-steroid acids which comprises heating acyclopentano-10,13- dimethylpolyhydrophenanthrene steroid having as thesole substituents on the 17-carbon atom of the steroid nucleus hydrogenand the groupmg H CH:

U N(CH3)3OH to split ofi trimethylamine and water to yield n -pregnenes,and oxidizing the thus formed vinyl group to a carboxyl group and forman etiosteroid acid.

8. The process of claim 7 in which the oxidation is an ozonization.

9. The process of claim 7 in which the starting quaternary ammoniumhydroxide is 3-acetoxyallo ternorcholanyltrimethyl ammonium hydroxide.

10. The process of claim 7 in which the starting quaternary ammoniumhydroxide is 3a.,12adiacetoxy ternorcholanyltrimethyl ammoniumhydroxide.

11. The process of preparing etio-steroid acids which comprisesconverting the COOH group of a cyclopentano 10,13dimethylpolyhydrophenanthrene steroid having as the sole substituents onthe 17-carbon atom of the steroi nucleus hydrogen and the grouping to anNH2 group by means of the Curtius degradation, converting the --NH2group to a -N-(CH3)3OH group, by exhaustive methylation followed bytreatment of the resulting quaternary ammonium halide with a metalcompound selected from the class consisting of alkali-metal hydroxidesand silver oxide, heating the resulting quaternary ammonium hydroxide tosplit off water and trimethylamine, and

oxidizing the thus formed vinyl group to a carboxyl group, therebyforming an etio-steroid acid.

12. The process which comprises heat decomposing 3hydroxy-5-ternor-cholenyltrimethyiammonium hydroxide to split ofitrimethylamine and water, subjecting the resulting 3-hydroxy-l 5,2O-pregnadiene to dehydrogenation by Oppenauers method to form 3-keto4,20-pregna- REFERENCES CITED 1O The following references are of recordin the .file Of this patent:

UNITED STATES PATENTS Number Name Date theme, and oxldlzmg the vinylgroup of said 420- pregnadiene to form 3-keto-4-etio-cho1enic acid.2481524 'Macphmamy 1949 13. The process of claim 12 in which the oxi- 5FOREIGN PATENTS dation of the vinyl group-is an ozonization. NumberCountry Date PERCY U 58,681 Denmark May 19, 1941 EDWIN 217,761Switzerland Feb. 16, 1942 227,069 Switzerland Aug. 2, 1943

1. THE PROCESS OF PREPARING ETIO-STEROID ACIDS WHICH COMPRISES TREATINGCYCLOPENTANO-10,13DIMETHYLPOLYHYDROPHENANTHRENE STEROID HAVING AS THESOLE SUBSTITUENTS ON THE 17-CARBON ATOM OF THE STEROID NUCLEUS HYDROGENAND THE GROUPING